UPR Pathways Combine to Prevent Hepatic Steatosis Caused by ER Stress-Mediated Suppression of Transcriptional Master Regulators

D. Thomas Rutkowski, Jun Wu, Sung Hoon Back, Michael U. Callaghan, Sean P. Ferris, Jahangir Iqbal, Robert Clark, Hongzhi Miao, Justin R. Hassler, Jamie Fornek, Michael G. Katze, M. Mahmood Hussain, Benbo Song, Jayanth Swathirajan, Junying Wang, Grace D.Y. Yau, Randal J. Kaufman

Research output: Contribution to journalArticlepeer-review

445 Scopus citations

Abstract

The unfolded protein response (UPR) is linked to metabolic dysfunction, yet it is not known how endoplasmic reticulum (ER) disruption might influence metabolic pathways. Using a multilayered genetic approach, we find that mice with genetic ablations of either ER stress-sensing pathways (ATF6α, eIF2α, IRE1α) or of ER quality control (p58IPK) share a common dysregulated response to ER stress that includes the development of hepatic microvesicular steatosis. Rescue of ER protein processing capacity by the combined action of UPR pathways during stress prevents the suppression of a subset of metabolic transcription factors that regulate lipid homeostasis. This suppression occurs in part by unresolved ER stress perpetuating expression of the transcriptional repressor CHOP. As a consequence, metabolic gene expression networks are directly responsive to ER homeostasis. These results reveal an unanticipated direct link between ER homeostasis and the transcriptional regulation of metabolism, and suggest mechanisms by which ER stress might underlie fatty liver disease.

Original languageEnglish
Pages (from-to)829-840
Number of pages12
JournalDevelopmental Cell
Volume15
Issue number6
DOIs
StatePublished - Dec 9 2008

Keywords

  • CELLBIO
  • HUMDISEASE

Fingerprint

Dive into the research topics of 'UPR Pathways Combine to Prevent Hepatic Steatosis Caused by ER Stress-Mediated Suppression of Transcriptional Master Regulators'. Together they form a unique fingerprint.

Cite this